RU2642962C9 - Parkinson's disease therapy with application of combination with fixed doses - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: group of inventions is a pharmaceutical composition for use in treatment of Parkinson's disease comprising a pharmaceutically acceptable carrier and a combination of fixed-dose pramipexole and rasagiline; and a method for production of a sustained release formulation comprising a combination of pramipexole and rasagiline or a pharmaceutically acceptable salt thereof with fixed doses thereof. This combination with fixed doses contains 0.05 to 1.0 mg of pramipexole and 0.055 to 1.0 mg of rasagiline.

EFFECT: group of invention allows to reduce the amount of side effects while maintaining high efficiency of the pharmaceutical composition by reducing the dose of pramipexole and maintaining a high dose of rasagiline.

19 cl, 4 dwg, 6 tbl, 4 ex

Description

FIELD OF TECHNOLOGY

[0001] The present invention relates to the field of neurodegenerative diseases and, in particular, relates to compositions and methods for treating Parkinson's disease.

BACKGROUND

[0002] Dopamine agonists have traditionally been used to treat Parkinson's disease; however, their use may be limited by adverse events of varying severity. The administration of dopamine agonists is usually associated with nausea, vomiting, and orthostatic hypotension. These side effects become more pronounced when using higher doses, but, as a rule, they can be reduced when using the scheme with delayed and complex titration. Pramipexole (as well as several other dopamine (DA) agonists) are also associated with impaired disorders, peripheral edema, psychosis and sedative effects that are difficult to control, thereby limiting the use of this drug. Razagilin, another drug used to treat Parkinson's disease, is generally well tolerated, but also has several safety concerns, in particular the risk of a cheese effect (hypertensive crisis) when eating foods rich in tyramine and a serotonin effect (excessive serotonin activity ) when used in combination with selective serotonin reuptake inhibitors and other antidepressants, which are traditionally prescribed for Parkinson's disease. If both of these drugs are considered, then higher doses of pramipexole are usually associated with an increased risk of severe undesirable effects, and therefore it is important for the attending physician to know the treatment strategies that provide maximum effectiveness in combating the symptoms of PD (Parkinson's disease) and while minimizing complications associated with motor activity, and adverse events caused by DA.

[0003] Pharma Two B found that combining agents with complementary mechanisms of action (ie, two different active agents with a symptomatic or neuroprotective effect) provides increased efficacy in controlling Parkinson's disease compared to that achieved with increased doses of each of the agents individually (international patent application WO 2009147681). Data from preclinical trials, previously obtained in Pharma Two B, suggest that the MAO-B inhibitor razagilin and dopamine agonist pramipexole in low doses have a synergistic effect, which manifests itself in an increase in the effectiveness of these drugs. Given that initiation of treatment using dopamine agonists is associated with a profile of relatively severe adverse events, current treatment methods include a low-dose titration regimen that is not expected to have a therapeutic effect but minimize side effects caused by immediate the beginning of the introduction of effective doses. In addition, undesirable effects are associated with long-term treatment using increased doses of a dopamine agonist. Thus, the use of a combination containing low doses of a dopamine agonist is preferred for many patients and can provide a highly active therapeutic effect, accompanied by minimal side effects.

SUMMARY OF THE INVENTION

[0004] According to some aspects, the present invention provides a pharmaceutical composition for use in the treatment of Parkinson's disease, comprising a pharmaceutically acceptable carrier and a fixed dose combination of pramipexole and rasagiline, said fixed dose combination containing a subtherapeutic dose of pramipexole and a subtherapeutic dose of razagilin, the dose of pramipexole is lower than or equal to the dose of rasagiline.

[0005] According to another aspect, the present invention provides methods for producing a sustained release (ER) composition of a combination of pramipexole and rasagiline or their pharmaceutically acceptable salts with fixed doses, comprising the steps of:

(i) dissolving the active agent containing pramipexole, rasagiline or both of these substances, optionally suitably mixed with a binding agent and / or a glidant, in a suitable solvent system to obtain a uniform suspension;

(ii) coating the suspension obtained in step (i) on inert pellets, such as inert nonpareil grains;

(iii) optionally applying an insulating / protective undercoat to pellets containing razagiline, pellets containing pramipexole, or pellets containing pramipexole and razagiline obtained in step (ii);

(iv) applying to the pellets obtained in stage (ii) or (iii) a sustained release coating layer that provides a sustained release of said pramipexole and rasagiline, thereby obtaining the indicated sustained release composition;

(v) optionally mixing the coated pellets obtained in step (iv) with a suitable excipient; and

(vi) filling capsules with said sustained release formulation or compressing said sustained release formulation into tablets, wherein said capsules or tablets have the desired ratio of pellets containing pramipexole to pellets containing rasagiline; or said capsules or tablets contain pellets containing pramipexole and razagilin;

thereby obtaining a sustained release formulation containing a combination of pramipexole and razagiline with fixed doses thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 shows the dissolution profile of a combination product.

[0007] FIG. Figure 2 shows the dose-dependent synergistic effect of pramipexole, razagilin and their combination on the level of dopamine in the brain of mice.

[0008] FIG. 3A-B show the results of a study of the pharmacokinetics of P2 B001 (FDC (fixed-dose combination) containing 1 mg of rasagiline and 0.75 mg of pramipexole) and their comparison with the corresponding commercial drugs, Azilect (1 mg of rasagiline) and Mirapex ER (0, 75 mg pramipexole), which were administered separately or in combination. Plasma concentrations (pg / ml) of pramipexole and razagilin are given.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention is based on the fact that it is possible to use a combination of very low doses of a dopamine agonist, in particular those doses that currently are generally not used for monotherapy, but used for titration, with different doses of a monoamine oxidase B inhibitor. (MAOV), razagilin, while you can achieve high efficiency due to the synergy of the mechanisms of action of these two drugs.

[0010] This fact allows a reduction in the dose of pramipexole and thus prevents the risk of adverse events caused by a dopamine agonist (DA), while maintaining comparable efficacy in higher doses in patients. Thus, it is possible to more accurately determine the best doses of rasagiline and pramipexole for use in combination, which are associated with a significant effect on Parkinson's disease and a good safety profile.

[0011] Thus, according to the present invention, a fixed-dose combination containing subtherapeutic doses of pramipexole and rasagiline or their pharmaceutically acceptable salts, i.e. the dose of pramipexole, which, when administered separately, does not have a significant therapeutic effect, and the dose of razagilin, which, when administered separately, does not have a significant therapeutic effect, where the dose of pramipexole is lower than or equal to the dose of rasagiline, is effective for the treatment of Parkinson's disease.

[0012] The term “fixed-dose combination” as used herein refers to a single composition containing two different drugs, in this case, rasagiline and pramipexole, in an exact ratio, namely, in specific fixed doses.

[0013] The term "subtherapeutic dose", as used herein, refers to a dose below the effective dosage level traditionally used in monotherapy to treat a disease, or to a dose that is currently generally not used in effective monotherapy, t. e. in the case of pramipexole and rasagiline, approximately 1 mg / day.

[0014] In particular, the molar ratio of pramipexole to rasagiline is selected from the range from 1: 1 to 1:20, from 1: 1 to 1:10, from 1: 1 to 1: 5, from 1: 1 to 1: 3, or from 1: 1 to 1: 2.

[0015] In specific embodiments, the molar ratio of pramipexole to rasagiline is selected from the range from 1: 1.1 to 1:20, from 1: 1.1 to 1:10, from 1: 1.1 to 1: 5, from 1 : 1.1 to 1: 3 or 1: 1.1 to 1: 2. In particular, this ratio is selected from the group consisting of 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1, 7, 1: 1.8, 1; 1.9, 1: 2.0, 1: 2.1, 1: 2.2, 1: 2.3, 1: 2.4, 1: 2.5, 1: 2.6, 1: 2.7, 1: 2.8, 1: 2.9 and 1: 3.0.

[0016] In specific embodiments, the fixed-dose combination contains from 0.05 mg to 1.0 mg of pramipexole and from 0.05 mg to 1.0 mg of rasagiline, provided that the dose of pramipexole is lower than or equal to the dose of rasagiline, as defined above .

[0017] In specific embodiments, the fixed-dose combination contains from 0.1 to 0.6 mg of pramipexole and from 0.1 to 0.75 mg of rasagiline.

[0018] In specific embodiments, the fixed-dose combination may comprise 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.105, 0 , 11, 0.115, 0.12, 0.125, 0.13, 0.135, 0.14, 0.145, 0.15, 0.155, 0.16, 0.165, 0.17, 0.175, 0.18, 0.185, 0.19 , 0.195, 0.2, 0.205, 0.21, 0.215, 0.22, 0.225, 0.23, 0.235, 0.24, 0.245, 0.25, 0.255, 0.26, 0.265, 0.27, 0.275 , 0.28, 0.285, 0.29, 0.295, 0.3, 0.305, 0.31, 0.315, 0.32, 0.325, 0.33, 0.335, 0.34, 0.345, 0.35, 0.355, 0 , 36, 0.365, 0.37, 0.375, 0.38, 0.385, 0.39, 0.395, 0.4, 0.405, 0.41, 0.415, 0.42, 0.425, 0.43, 0.435, 0.44 , 0.445, 0.45, 0.455, 0.46, 0.465, 0.47, 0.475, 0.48, 0.485, 0.49, 0.495, 0.5, 0.505, 0.51, 0.515.0.52, 0.525 , 0,53,0,535, 0,54, 0,545, 0,55,0,555, 0,56, 0,565, 0,57,0,575, 0,58, 0,585, 0,59, 0,595, 0,6, 0,605, 0 , 61, 0.615, 0.62, 0.625, 0.63, 0.635, 0.64, 0.645, 0.65, 0.655, 0.66, 0.665, 0.67, 0.675, 0.68, 0.685, 0.69 , 0.695 , 0.7, 0.705, 0.71, 0.715, 0.72, 0.725, 0.73, 0.735, 0.74, 0.745, 0.75, 0.755, 0.76, 0.765, 0.77, 0.775, 0 78, 0.785, 0.79, 0.795, 0.8, 0.805, 0.81, 0.815, 0.82, 0.825, 0.83, 0.835, 0.84, 0.845, 0.85, 0.855, 0.86 , 0.865, 0.87, 0.875, 0.88, 0.885, 0.89, 0.895, 0.9, 0.905, 0.91, 0.915, 0.92, 0.925, 0.93, 0.935, 0.94, 0.945 , 0.95.0.955, 0.96, 0.965, 0.97.0.975, 0.98, 0.985, 0.99, 0.995 or 1 mg of pramipexole and 0.05, 0.055, 0.06, 0.065, 0.07 , 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.105, 0.11, 0.115, 0.12, 0.125, 0.13, 0.135, 0.14, 0.145, 0.15, 0.155 , 0.16, 0.165, 0.17, 0.175, 0.18, 0.185, 0.19, 0.195, 0.2, 0.205, 0.21, 0.215, 0.22, 0.225, 0.23, 0.235, 0 24, 0.245, 0.25, 0.255, 0.26, 0.265, 0.27, 0.275, 0.28, 0.285, 0.29, 0.295, 0.3, 0.305, 0.31, 0.315, 0.32 , 0.325, 0.33, 0.335, 0.34, 0.345, 0.35, 0.355, 0.36, 0.365, 0.37, 0.375, 0.38, 0.385, 0.39, 0.395, 0.4, 0.405 , 0.41, 0.415, 0.42, 0.425, 0.43, 0.435, 0.44, 0.445, 0.45, 0.455.0.46, 0.465, 0.47, 0.475.0.48, 0.485, 0 , 49, 0.495, 0.5, 0.505, 0.51, 0.515, 0.52, 0.525, 0.53, 0.535, 0.54, 0.545, 0.55, 0.555, 0.56, 0.565, 0.57, 0.575, 0.58, 0.585, 0.59, 0.595, 0.6, 0.605, 0.61, 0.615, 0.62, 0.625, 0.63, 0.635, 0.64, 0.645, 0.65, 0.655, 0, 66, 0.665, 0.67, 0.675, 0.68, 0.685, 0.69, 0.695, 0.7, 0.705, 0.71, 0.715, 0.72, 0.725, 0.73, 0.735, 0.74, 0.745, 0.75, 0.755, 0.76, 0.765, 0.77, 0.775, 0.78, 0.785, 0.79, 0.795, 0.8, 0.805, 0.81, 0.815, 0.82, 0.825, 0.83, 0.835, 0.84, 0.845, 0.85, 0.855, 0.86, 0.865, 0.87, 0.875, 0.88, 0.885, 0.89, 0.895, 0.9, 0.905, 0, 91, 0.915, 0.92, 0.925, 0.93, 0.935, 0.94, 0.945, 0.95, 0.955, 0.96, 0.965, 0.97, 0.975, 0.98, 0.985, 0.99, 0.995 or 1 mg of rasagiline, provided that the dose of pramipexole is lower than or equal to the dose of rasagiline, as defined above.

[0019] For clarity, but not limitation of the scope of the proposed invention, unless otherwise indicated, it should be understood that all numerical values expressing the amount, percentage, or proportion, as well as other numerical values indicated in the present description, are used in all cases along with the term “about.” Accordingly, the numerical parameters given in the present description are approximate and may vary depending on the desired end result. For example, each numerical parameter can be considered taking into account the number of indicated significant digits, as well as the use of the usual rounding rules.

[0020] It should be understood that any dose ranges, ranges of amounts, ranges of concentrations, ranges of percentages or ranges of ratios described herein include doses, concentrations, percentages, or ratios having any value not beyond this range, and also beyond its boundaries, but not more than one tenth of the value of the upper or lower limit of the specified range, or a fraction of the specified value, such as one tenth and one hundredth of the numerical value, if not specified it is different.

[0021] In other embodiments, pramipexole and rasagiline are formulated in a sustained release (ER) formulation. The term “sustained release” is used interchangeably herein with the terms “long-term action”, “repeated action”, “controlled release” and “delayed release”, and it refers to the release of an active agent at predetermined intervals or to a gradual release, thus that the active agent contained is available for an extended period of time after oral administration.

[0022] In specific embodiments, the gradual release of all or substantially all of the pramipexole and rasagiline included in the fixed-dose combination from the sustained-release formulation occurs within 24 hours.

[0023] The pharmaceutical composition may take the form of a monolithic matrix; tablets, preferably a double or multilayer tablet, matrix tablet, disintegrating tablet, soluble tablet or chewable tablet; capsules or sachets, preferably filled with granules, grains, balls or pellets; or a depot system based on a biodegradable polymer such as poly (D, L-lactide) (PLA), polyglycolide (PHA) and a copolymer of D, L-lactide and glycolide (PLHA), and it can be prepared for oral administration.

[0024] The active agent can be suitably mixed with a binding agent and / or a glidant in a suitable solvent system to give a uniform suspension, and then the resulting suspension can be applied to inert pellets to give a thin coating. According to the present invention, rasagiline and pramipexole can be dissolved in separate solvents and sprayed separately on various pellets to obtain pellets containing razagilin and pellets containing pramipexole; or each individual solution can be sprayed onto the same pellets to produce pellets containing razagilin and pramipexole. Alternatively, rasagiline and pramipexole can be dissolved in a common solvent to obtain a common homogeneous solution, or separate solutions can be mixed to obtain a common homogeneous solution, after which a common homogeneous solution can be sprayed onto pellets to obtain pellets containing razagilin and pramipexole.

[0025] In the next step, which is optional, pellets containing razagilin, pellets containing pramipexole, or pellets containing razagilin and pramipexole are coated with an insulating / protective subcoat layer, after which the pellets are coated with a sustained release coating, which provides a sustained release of rasagiline and pramipexole, thus obtaining the specified composition with a prolonged release. Coated pellets can then be mixed with a suitable adjuvant, and finally, the capsules can be filled with a sustained release formulation or compressed into tablets, wherein said capsules or tablets have the desired ratio of pellets containing rasagiline to pellets containing pramipexole; or said capsules or tablets contain pellets containing razagilin and pramipexole.

[0026] The desired ratio, as defined above in the present description, can be obtained using any method that provides the desired result, such as, but not limited to, weighing, measuring volume, or counting the number of pellets containing razagiline and pellets containing pramipexole individually and filling them with a capsule, or compressing a tablet having a desired mass, volume or amount of pellets containing each active agent. Preferably, the pellets are weighed separately and filled into the desired ratio of the capsule or compressed into tablets or weighed together in a predetermined ratio, after which the mixture is weighed and filled into the capsule. In the case of pellets containing razagilin and pramipexole, the ratio is determined at the stage of coating on inert pellets, in which a solution with the desired ratio of two agents is sprayed on inert pellets, or two separate solutions are sprayed layer by layer on inert pellets in the desired ratio.

[0027] Thus, in specific embodiments, a pharmaceutical composition according to the present invention comprises sustained release pellets comprising (i) an inert pellet core; (ii) a drug layer covering said pellet core, said drug layer containing an active agent containing razagilin, pramipexole, or both of these substances, or pharmaceutically acceptable salts thereof, optionally mixed with a binder and / or film-forming polymer and additionally optionally mixed with a glidant; (iii) an optionally insulating / protective subcoat layer covering said drug layer; and (iv) a sustained release layer covering said subcoat layer, if used, or covering said drug layer.

[0028] An ER pellet according to the present invention may optionally comprise an insulating / protective subcoating layer covering said drug layer. The objective of this subcoat layer is to isolate the active substance layer from the external ER coating and to protect it from possible interaction with the active agent, which may affect its stability and lead to the formation of decomposition products of the active pharmaceutical ingredient (API). In specific embodiments, the sub-cover layer comprises a film-forming polymer and, optionally, a glidant.

[0029] An ER pellet according to the present invention comprises an outer ER coating layer, also referred to herein as a “functional layer”, covering the sub-coating layer, if present, or the drug coating layer.

[0030] In specific embodiments, the ER coating layer comprises at least one pH independent polymer, i.e. a water-swellable / water-insoluble / hydrophobic polymer, and optionally a pore-forming agent, wherein the sustained release pellet has pH independent in vitro release characteristics. In other embodiments, the functional layer comprises a pH independent polymer, a hydrophilic release modulator polymer acting as a pore-forming agent, and, optionally, a hydrophobic or hydrophilic plasticizer and / or glidant. In further specific embodiments, the ER coating layer comprises a mixture of a pH dependent enteric coating polymer and a pH independent polymer, the sustained release pellet having approximately zero order in vitro release characteristics at an acidic or physiological pH, i.e. at pH no more than 7.4.

[0031] Binding agents for pharmaceutical use are hydrophilic substances such as sugars and natural and synthetic polymers used to formulate solid dosage forms due to their adhesive and cohesive properties. The task of binding agents is to contribute to an increase in size by increasing the cohesive ability of the powders, thereby providing pellets and tablets with the necessary adhesion strength. Despite the fact that binding agents improve the appearance, hardness and abrasion resistance of these preparations, they do not affect the rate of disintegration of the tablets or the dissolution rate of the active substances. Binders of natural origin that have traditionally been used in the past include gum arabic, gelatin, starch and hydrolyzed starch. These substances have been replaced by synthetic binding agents, the most important of which are povidone and various cellulose derivatives. Examples of binding agents that can be mixed with the active agent in the drug coating layer ER-pellets according to the present invention include, but are not limited to, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose, and combinations thereof.

The binding agent can be contained in an amount of from 0.5% to 20%, preferably from 0.5% to 10% by weight of the total weight of the pellets.

[0032] The term “film-forming polymer,” as used herein, refers to polymers capable of curing to form adhesive films. In addition, the physical property of these polymers, which is essential for their use as a coating, is the ability to form films or impart certain adhesive properties to the material on which they are applied. Examples of film-forming polymers include, but are not limited to, PVP, HPMC, HPC, microcrystalline cellulose, and combinations thereof. The film-forming polymer, if present in the drug layer, may be present in an amount up to 90% by weight of the total weight of the drug layer, preferably from 0.5% to 20% by weight of the total weight of the pellet. The amount of film-forming polymer in the under-cover layer can be up to 100% by weight of the total weight of the under-cover layer, preferably from 0.5% to 10% by weight of the total weight of the pellet.

[0033] In order to increase the flowability of granules and powders by reducing friction and surface charge, glidants are typically added to pharmaceutical compositions. In addition, they are used as anti-caking agents during the coating process. Specific slip agents, such as talc and glyceryl monostearate, are traditionally used in coated formulations as anti-stick agents that reduce the tendency to stick when the product temperature is lowered. Other glidants, such as colloidal silicon dioxide, provide the desired flow characteristics that are used to improve the flow properties of dry powders in a number of processes, such as tablets and capsules, due to their small particle size and large specific surface area. Non-limiting examples of glidants include talc, in particular finely divided talc, colloidal silicon dioxide, glyceryl monostearate, and combinations thereof.

[0034] Glidants, if contained in the drug layer, may be present in an amount up to 30% by weight of the total weight of the drug layer, preferably from 0.5% to 5% by weight of the total weight of the pellet. The amount of glidant, if present in the sub-cover layer, can be up to 10% by weight of the total weight of the sub-cover layer, preferably from 0.5% to 5% by weight of the total weight of the pellet.

[0035] Examples of pH independent polymers that may be contained in an ER pellet according to the present invention include, but are not limited to, ethyl cellulose, Surelease®, acrylic ester and methacrylic acid ester copolymers such as Eudragit RL (Eudragit® RL) (poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride), 1: 2: 0.2), Eudragit RS (Eudragit® RS) (poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride), 1: 2: 0.1), Eudragit NE (Eudragit® NE) (poly (ethyl acrylate, methyl methacrylate), 2: 1) and combinations thereof. The pH independent polymer may be present in an amount of from 10% to 50%, preferably from 10% to 30% by weight of the total weight of the pellet.

[0036] Examples of pH-dependent enteric coating polymers that may be contained in an ER pellet according to the present invention include, but are not limited to, Eudragit S (Eudragit® S) (poly (methacrylic acid, methyl methacrylate), 1: 2), Eudragit L 55 ( Eudragit® L 55) (poly (methacrylic acid, ethyl acrylate), 1: 1), Collicoat (Kollicoat®) (graft copolymer of polyethylene glycol with polyvinyl alcohol), 1: 1), hydroxypropyl methylcellulose phthalate (FGPMTS), alginates, carboxymethyl and their combinations . The pH dependent enteric coating polymer may be present in an amount of from 10% to 50%, preferably from 10% to 30%, by weight of the total weight of the pellets.

[0037] The term "pore-forming agent" as used herein refers to a substance that dissolves in the body and thus forms open pores in the matrix, which increases the diffusion rate of the active agent through the coating layer. The size of the resulting pores can be controlled to some extent by the size of the solid particulate material used. For pore uniformity, the particulate material can be sieved through sieves with an increasingly smaller mesh size to produce particles having a size in the desired range. The pore-forming agent that may be contained in ER-pellets according to the present invention is an inorganic or organic substance, including, for example, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), HPMC, HPC, methyl cellulose, 1,2-propylene glycol, lactose, sucrose , talc, in particular finely divided talc, and combinations thereof. The pore-forming agent may be contained in an amount of from 0.1% to 20%, preferably from 0.1% to 10% by weight of the total weight of the pellet.

[0038] The term “hydrophilic release modulator polymer” as used herein refers to a water-soluble polymer that controls the release of the active agent. However, in specific embodiments, the hydrophilic release polymer modulator contained in the ER coating layer of the ER pellets according to the present invention actually acts as a pore-forming agent. Examples of hydrophilic release modulating polymers include, but are not limited to, PVP, PEG, HPMC, HPC, and combinations thereof. The hydrophilic polymer-modulator release may be contained in an amount of from 0.1% to 20%, preferably from 0.1% to 10% by weight of the total weight of the pellets.

[0039] The term “plasticizer” as used herein includes any compounds or combinations of compounds capable of imparting plasticity or softening to a polymer used in an ER pellet according to the present invention. Upon receipt of the ER coating layer, the plasticizer can reduce the melting point or glass transition temperature (softening temperature) of the polymer used or a combination of polymers; can expand the range of the average molecular weight of the specified polymer or combination of polymers and can further reduce the viscosity of the specified polymer or combination of polymers for more convenient processing of the coating solution. Non-limiting examples of plasticizers include dibutyl sebacate, dibutyl phthalate, citric acid esters such as triethyl citrate and triacetin; propylene glycol; low molecular weight poly (alkylene oxides) such as PEG, poly (propylene glycols) and poly (ethylene / propylene glycols); and their combinations. Plasticizers can be contained in an amount of from 0.1% to 20%, preferably from 0.1% to 10% by weight of the total weight of the pellets.

[0040] An ER pellet according to the present invention may further comprise inactive ingredients, such as an osmotic pressure / tonicity regulator. These agents are traditionally used for time-controlled disintegration if pulsed drug delivery is required. Examples of suitable osmotic pressure / tonicity adjuvants that can be used to produce ER pellets include, but are not limited to, sodium chloride and mannitol. The osmotic pressure / tonicity regulator, if present in the ER pellet, may be present in an amount up to 20%, preferably from 0.5% to 10% by weight of the total weight of the pellet.

[0041] In the specific embodiment proposed herein, the ER pellets provided herein comprise an inert pellet core; a drug layer containing the active agent in admixture with PVP used as a film-forming polymer / binding agent and highly dispersed talcum powder used as a glidant; and an ER coating layer containing ethyl cellulose as a pH independent polymer and PEG as a pore forming agent, wherein the amount of said film forming polymer / binding agent is up to 90% by weight of the total weight of the drug layer or from 0.5% to 20% by weight of the total mass of pellets; the amount of said glidant is up to 30% by weight of the total weight of the drug layer or from 0.1% to 10% by weight of the total weight of the pellet; the amount of said pH-independent polymer is from 50% to 90% by weight of the total weight of the ER coating layer or from 10% to 30% by weight of the total weight of the pellet; and the amount of said pore-forming agent is from 1% to 20% by weight of the total weight of the ER coating layer or from 0.1% to 10% by weight of the total weight of the pellet.

[0042] In other specific embodiments proposed herein, an ER pellet according to the present invention comprises an inert pellet core; a drug layer containing the indicated active agent in admixture with PVP used as a film-forming polymer / binding agent and highly dispersed talcum powder used as a glidant; an insulating / protective undercover layer containing PVP as a film-forming polymer; and an ER coating layer containing ethyl cellulose as a pH independent polymer, PEG as a pore forming agent and highly dispersed talc as a glidant, wherein the amount of said film forming polymer / binding agent included in said drug layer is up to 90% by weight of the total weight of the drug layer or from 0.5% to 20% by weight of the total weight of the pellets; the amount of said glidant agent included in said drug layer is up to 30% by weight of the total weight of the drug layer or from 0.1% to 10% by weight of the total weight of the pellet; the amount of the specified film-forming polymer that is part of the specified sub-cover layer is up to 100% by weight of the total weight of the sub-cover layer or from 0.5% to 20% by weight of the total weight of the pellet; the amount of said pH-independent polymer is from 50% to 90% by weight of the total weight of the ER coating layer or from 10% to 30% by weight of the total weight of the pellet; the amount of the specified pore-forming agent is from 1% to 20% by weight of the total weight of the ER coating layer or from 0.1% to 10% by weight of the total weight of the pellet; and the amount of said glidant agent included in said ER coating layer is from 0.1% to 20% by weight of the total mass of the ER coating layer or from 0.1% to 10% by weight of the total pellet mass .

[0043] In specific embodiments, sustained release pellets are mixed with one or more suitable adjuvants and either placed in capsules or compressed into tablets, said capsules or tablets containing extended release pellets containing extended release pellets containing rasagiline, and sustained release pellets containing pramipexole, or sustained release pellets containing razagilin and pramipexole.

[0044] These capsules or tablets may be prepared using any suitable technology known in the art.

[0045] Examples of suitable adjuvants that can be used to prepare an oral pharmaceutical composition include, but are not limited to, silicas, as well as other glidants known in the art, such as defined above.

[0046] Tablet excipients supplement the volume of the tablet or capsule, which makes it practical to obtain them, as well as convenient use by the consumer. By increasing the total volume, fillers provide a final product volume suitable for use by the patient. A good filler should be inert, compatible with other components of the composition, non-hygroscopic, relatively cheap, compactable and preferably tasteless or tasting good. Plant cellulose (pure plant fiber) is a popular filler for tablets or hard gelatine capsules. Dibasic calcium phosphate is another popular tablet excipient. A variety of vegetable fats and oils can be used in soft gelatin capsules. Tablet excipients include, for example, lactose, mannitol / Parteck®, sorbitol, starch, and combinations thereof.

[0047] The baking powder expands and dissolves in a wet state, which leads to the disintegration of the tablets in the digestive tract and the release of the active ingredients for absorption. Types of disintegrants include water reuptake agents and tablet disintegration promoters. These substances provide rapid destruction of the tablet into smaller fragments when brought into contact with water, which contributes to dissolution. Non-limiting examples of disintegrants include crosslinked polyvinylpyrrolidone (crospovidone), sodium / calcium carboxymethyl cellulose (CMC), sodium croscarmellose, low substitution hydroxypropyl cellulose, sodium bicarbonate, starch, sodium starch glycolate, and combinations thereof.

[0048] To improve certain process characteristics, small amounts of lubricants are added to the tablet or capsule formulations. More specifically, these agents prevent the ingredients from sticking together, as well as sticking to the punch used to make the tablets or to the parts of the capsule filling machine. Lubricants also provide low friction between the solid and the walls of the mold upon receipt of the tablets and their removal from the mold. Examples of lubricants include, but are not limited to, glyceryl behenate, stearic acid, talc, zinc stearate, calcium stearate, and combinations thereof.

[0049] According to another aspect, the present invention relates to a method for treating Parkinson's disease, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition for use to treat Parkinson's disease, comprising a pharmaceutically acceptable carrier and a fixed dose combination of pramipexole and rasagiline, wherein the specified combination with fixed doses contains a subtherapeutic dose of pramipexole and a subtherapeutic dose of rasagiline, while the dose of pra ipeksola less than or equal to a dose of rasagiline.

[0050] The terms “treat,” “treat,” and “provide a significant therapeutic effect,” as used interchangeably herein, refer to terminating, slowing, reducing the severity, or minimizing a neurodegenerative process in nigrostriatal neurons (neuroprotective therapy), eliminating or decreasing biochemical imbalance, increased dopamine synthesis, stimulation of dopamine receptor activity and the release of dopamine from the presynaptic space and / or inhibition of reuptake that presynaptic dopamine receptors and dopamine catabolism. These terms may also refer to improving or slowing the worsening of symptoms of Parkinson's disease, such as tremors, slow movement (bradykinesia), restless legs syndrome, muscle stiffness, poor posture and balance, automatic movement disorders, speech changes, sleep disturbances and / or quality problems life (QOL), to the elimination or reduction of symptoms of physical, cognitive or mental disorders in Parkinson's disease and even possibly to slow down or stop the progression of dementia.

[0051] An improvement, decrease, or slowdown in the worsening of symptoms of Parkinson's disease can be fixed by determining one or more acceptable parameters before and during the treatment period, such as, but not limited to, the Parkinson's Unified Rating Scale Rating Index (UPDRS) index, auxiliary activity indices daily life (ADL) and UPDRS motor skills, Beck Depression Inventory® II (BDI-II), symptoms on the International Restless Leg Syndrome Rating Scale (IRLS), patient quality of life questionnaire Parkinsinson's Disease 39 (PDQ39), General Clinical Impression (CGI).

[0052] According to other aspects, the present invention relates to fixed-dose combinations, as defined hereinabove, for use in the treatment of Parkinson's disease; or for the manufacture of a medicament for the treatment of Parkinson's disease.

[0053] According to another aspect, the present invention provides a method for producing a sustained release composition comprising a combination of pramipexole and rasagiline or pharmaceutically acceptable salts with fixed doses thereof, comprising the steps of: (i) dissolving the active agent containing pramipexole, rasagiline or both of these substances optionally mixed with a binding agent and / or glidant in a suitable solvent system to form a uniform suspension; (ii) coating the suspension obtained in step (i) on inert pellets, such as inert nonpareil grains; (iii) optionally applying an insulating / protective undercover layer to pellets containing razagiline, pellets containing pramipexole, or pellets containing razagiline and pramipexole obtained in step (ii); (iv) applying to the pellets obtained in step (ii) or (iii) a sustained release coating layer that provides a sustained release of said rasagiline and pramipexole, thereby obtaining the indicated sustained release composition; (v) optionally mixing the coated pellets obtained in step (iv) with a suitable excipient; and (vi) filling capsules with said sustained release formulation or compressing said sustained release formulation into tablets, wherein said capsules or tablets have the desired ratio of razagilin-containing pellets to pramipexole-containing pellets; or said capsules or tablets contain pellets containing razagilin and pramipexole, thereby obtaining a sustained release composition containing a combination of razagilin and pramipexole with fixed doses thereof.

[0054] The invention will now be illustrated by the following non-limiting examples.

EXAMPLES

Example 1: Preparation and dissolution profile of a combined product.

[0055] Each component was separately formulated (Tables 1 and 2) and grains having an appropriate weight were encapsulated to give a dose containing 0.6 mg of pramipexole and 0.75 mg of rasagiline.

Analysis Method — Dissolution Study of Combined Product

[0056] Using the method of high performance liquid chromatography (HPLC) used for quantitative analysis, the dissolution profile of the active pharmaceutical ingredients (API), pramipexole (PPX) and rasagiline (RAS) included in the sustained release pellet (ER) were evaluated ) placed in the capsule.

[0057] The contents of one capsule or one sample of a dose of beads (pellets) were placed in a basket rotating inside a vessel containing a medium at a certain constant speed and at a certain constant temperature. The sample was dissolved in the solvent medium over a period of time at a rate that was reflected in the release profile of the composition, thus, the solution contained different concentrations of APIs at different points in time. Samples were taken automatically or manually at specific points in time at certain intervals, filtered through a 20 μm PE filter, cat. No. 400111, Sun Sri, and quantified by comparison with reference standard solutions.

[0058] The conditions used in the experiment described in table 3 were as follows:

• Device: 1 (baskets)

• Medium: Artificial Intestinal Juice (IFS), a buffer simulating intestinal conditions

• Speed: 100 rpm

• Temperature: 37 ° C ± 0.5 ° C

[0059] The amount of dissolved RAS and PPX was determined by HPLC.

Analysis Results - Dissolution Study of Capsule with Combined Product

Example 2: In vivo drug study on an MPTP model of Parkinson's disease

Materials and methods

Models. To identify possible pathological mechanisms in the disease, it is necessary to use experimental models of Parkinson's disease (PD). In addition to this task, such models are important for the development and study of new pharmacological or other treatment strategies.

[0060] The MPTP model in mice. A significant part of biochemical data obtained in studies after autopsy of the brain, as well as in animal models, indicates the development of oxidative stress in the black substance, which can cause dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary phenomenon. However, the oxidative stress caused by the MPTP neurotoxin (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is used in animal models to study the process of neurodegeneration in order to develop antioxidant neuroprotective drugs.

[0061] The MPTP neurotoxin is transformed in the brain into a positively charged MPP + (1-methyl-4-phenylpyridinium) molecule under the action of the MAO-B enzyme, which causes parkinsonism in primates by killing certain neurons that produce dopamine in the black substance. It acts by disrupting oxidative phosphorylation in the mitochondria, which leads to the consumption of ATP and cell death. It also inhibits catecholamine synthesis, lowers dopamine and cardiac norepinephrine, and inactivates tyrosine hydroxylase.

[0062] Experiment Procedure: Male C57B1 / 6 mice weighing 20 +/- 1 g (6-10 mice in the group) were used. MPTP was administered by intraperitoneal (i.p.) injection in the form of a 40 mg / kg dose for 5 days. As a control, mice that were not injected with MPTP and were injected with saline, and also mice that were injected with MPTP and then injected with saline (but not the drug), were used. Medicines, razagilin (0.15 mg / kg) and pramipexole (3 different doses, 0.12, 0.1 and 0.075 mg / kg), were administered individually or as 3 combinations of razagilin and pramipexole with their fixed doses. Fixed-dose combinations contained a constant 0.15 mg / kg dose of rasagiline and 3 different doses of pramipexole, as indicated above. Both drugs were dissolved in saline from the mother liquors to obtain the desired final dose used in combination. The introduction of drugs was carried out by daily intraperitoneal (ip) injection 30 minutes before the introduction of MPTR. The drug was administered for 12 days. The effect of treatment was determined by measuring the level of dopamine and its metabolites (dihydroxyphenylacetic acid and homovanilinic acid) in the left and right striatums collected from mice at the end of the experiment.

[0063] The study included 9 groups of 6-10 mice each. To start the simulated parkinsonism, mice were injected with MPTP, and they were also given combinations containing a constant dose of rasagiline and various doses of pramipexole. As a control, mice that were not injected with MPTP and were injected with saline, and also mice that were injected with MPTP and then injected with saline (but not the drug), were used. The groups were treated according to table 4 above. The study design is shown in table 5.

[0064] Sample preparation for HPLC analysis of dopamine and metabolites. Striatum tissue samples were homogenized in ice in 500 μl homogenization buffer (0.1 M perchloric acid, 0.02% EDTA and 1% EtOH) using the OMNI Tip homogenization kit manufactured by OMNI International (intermediate speed, 3 × 10 seconds at intervals for 5 seconds). The homogenates were sonicated for 5 minutes, then centrifuged at 15,000 rpm at 4 ° C for 15 minutes. The supernatant was transferred to fresh tubes and the dopamine content was analyzed by HPLC.

[0065] The results of this experiment are shown in Figure 2. The dopamine level in the brain of mice that were not injected with MPTP was defined as 100%, while the dopamine level in mice with PD caused by MPTP injected with saline was determined as 0%. The graph shows the effect of various treatments on dopamine levels compared to saline. It is clearly seen that FDC has a high synergy, where the action of rasagiline and all three doses of pramipexole when administered separately was very low, while the combination containing the same doses was highly effective and, it should be noted, was significantly more effective compared to with the combined effectiveness of both components. The effect of the combination depends on the dose, where the effectiveness increases with increasing doses of pramipexole, however, the dose-response relationship is significantly more pronounced compared with the dose-response relationship with the separate administration of increasing doses of pramipexole. This means that the addition of rasagiline has not just an additive effect, and we can assume that under these conditions the combination has a strong synergistic effect.

[0066] Thus, the results of the study of mice clearly show that the introduction of drugs in the form of a combination with a fixed dose, which is part of the combined product according to the present invention, where the introduction of these doses individually has a very low efficiency or is ineffective, has a therapeutic effect, which exceeds the sum of the therapeutic effects exerted by these drugs individually, which indicates a synergistic effect, is probably determined their complementary biological mechanisms. This suggests that when conducting human trials using subtherapeutic doses or doses that are lower than those effective when used in monotherapy, a significant effect can be achieved, which can be expected based on the results of a study of mice.

Example 3: Phase I Pharmacokinetics Study with Healthy Volunteers

[0067] Pharma Two B performed a four-way cross-sectional study of fasting healthy adult volunteers, comparing the effects of a single dose of marketed rasagiline with non-sustained release (Azilect, 1 mg) sold on the market of pramipexole with prolonged release (Mirapex ER, 0, 75 mg), both marketed drugs taken together and a sustained release combination product offered by Pharma Two B containing doses of rasagiline (1 mg) and pram eksola (0.75 mg) of equal doses in commercially available products for monotherapy.

[0068] Co-administration of selected drugs. Assessment of plasma pramipexole concentration showed the absence of a statistically significant effect of concomitant administration of razagiline on the pharmacokinetics of pramipexole. The combined administration of Mirapex ER and Azilect resulted in only a 4% decrease in C _{max of} pramipexole and a 3% increase in AUC _inf . Similarly, concomitant administration of pramipexole did not have a statistically significant effect on the pharmacokinetics of rasagiline. C _max and AUC _inf rasagiline increased by 3% and 4%, respectively, when it was co-administered with Mirapex ER (table 6).

[0069] Comparison of co-administration of individual drugs and combination product. The proposed sustained release product (FDC) had a slightly different (statistically insignificant) pharmacokinetics profile of pramipexole compared to that observed with the combined administration of Mirapex ER and Azilect (Cmax decreased by 15%, and AUC _inf increased by 10% (Table 6 and Fig. 3A-B)).

[0070] The pharmacokinetics profile of rasagiline, which is a component of the combined product, reflects differences in composition (sustained release formulation compared to non-sustained release formulations) compared to formulations used in other study groups. C _{max of} rasagiline, which is part of the combined product, was approximately 95% lower, while AUC _inf was 22% lower compared to the values achieved with the joint administration of Azilect with Mirapex ER.

[0071] If we consider the results of the studies obtained in the complex, we can see that the combined administration of pramipexole and razagiline did not affect the pharmacokinetics profiles of the two drugs, and the product in the form of a combined composition ensured the delivery of pramipexole similar to Mirapex ER. Also, the product in the form of a combined composition provided a prolonged release of rasagiline and did not significantly affect the overall effect of the drug. In addition, these data suggest the presence of an effective safety profile of a combination of drugs.

Example 4. Clinical Phase IIB Study to Evaluate a Fixed-Dose Combined Product Offered by the Applicant

[0072] The Applicant intends to show that his combination product has a beneficial effect, is well tolerated and has a good safety profile in patients at an early stage of Parkinson's disease.

[0073] This is achieved through a study to determine the optimal dose, which compares 3 doses of the combined product proposed by Pharma 2b and placebo to determine the safety, tolerability and effectiveness of this therapy and to identify the best combination containing small doses of drugs that provides maximum clinical efficacy and at the same time reduced side effects.

[0074] The main task is to determine the effectiveness, safety and tolerance of 3 different doses of the combined product, and the secondary task is to determine the effect of the combined product on sleep, mood and quality of life (QOL).

[0075] Research plan. The study conducted by the applicant is a randomized, double-blind, placebo-controlled, multicenter study of the PV phase in parallel groups to determine the optimal dose among 3 doses of the combination. Each component is used in doses lower than those traditionally used to treat patients at an early stage of Parkinson's disease. The study population included 200 volunteers among patients at an early stage of Parkinson's disease (the diagnosed Parkinson's disease corresponds to the clinical diagnostic criteria of the brain bank of the British society of Parkinson's disease and the stage of Parkinsonism according to the modified Hen and Yara scale <3), which were selected in general hospitals and academic clinics in the USA and Israel, a total of 45 institutions were involved, of which 40 from the USA and 5 from Israel.

[0076] Voluntary patients were randomly assigned to one of four groups (50 subjects per group) and given one of three different doses of the combined product, where the dose of rasagiline varies from 0.1 mg to 0.75 mg and the dose of pramipexole varies from 0.1 to 0.6 mg, or the corresponding placebo.

[0077] All drugs were taken orally once a day in the morning before breakfast at about the same time every day.

[0078] The study is divided into 3 phases: a screening phase (maximum 4 weeks), a treatment and maintenance phase of the dose (12 weeks), and an additional safety assessment phase (2 weeks).

[0079] The following end-points are measured: effectiveness, the primary end-point of which is a change in the overall index according to the Unified Rating Scale for Parkinson's Disease Rating (UPDRS) (defined as the sum of the indices of Part II — activity of everyday life — and Part III — assessment of motility — ranging from 0 to 160) from the baseline to the last visit (12 weeks). Secondary endpoints include changes in supporting daily life activity indexes (ADLs) and UPDRS motility, the results of the Beck Depression Inventory® II (BDI-II), and the quality of life questionnaire for patients with Parkinsinson 39 disease (PDQ39) , the overall clinical impression (CGI) of the subject and the researcher in the period from baseline to 12 weeks. Safety is planned to be determined using reports of adverse events (frequency and quantity), as well as scales for sleep quality, daytime sleepiness, depression, suicidality, impulse control. Portability is planned to be determined by the number of subjects divided into groups, in percent, who will complete the test. After a 12-week trial, UPDRS indices and clinical safety assessments are planned every 2-4 weeks. Using a primary efficacy analysis, it is planned to compare the groups that were administered the active dose and placebo using a mixed model of repeated measurements (MMRM).

Claims (50)

1. A pharmaceutical composition for use in the treatment of Parkinson's disease, comprising a pharmaceutically acceptable carrier and a fixed dose combination of pramipexole and razagiline, said fixed dose combination comprising from 0.05 to 1.0 mg of pramipexole and from 0.055 to 1.0 mg of rasagiline while the dose of pramipexole is lower than the dose of rasagiline. 2. The pharmaceutical composition according to claim 1, characterized in that the molar ratio of pramipexole to rasagiline is selected from the range of 1: 1.1-1: 20; 1: 1.1-1: 10; 1: 1.1-1: 5; 1: 1.1-1: 3 or 1: 1.1-1: 2. 3. The pharmaceutical composition according to claim 2, characterized in that said fixed-dose combination contains from 0.1 to 0.6 mg of pramipexole and from 0.1 to 0.75 mg of rasagiline. 4. The pharmaceutical composition according to claim 1, which is a composition for oral administration. 5. The pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that said pramipexole and rasagiline are part of a sustained release composition. 6. The pharmaceutical composition according to claim 5 in the form of a monolithic matrix; tablets, preferably a double or multilayer tablet, matrix tablet, disintegrating tablet, soluble tablet or chewable tablet; capsules or sachets, preferably filled with granules, grains, balls or pellets; or a depot system based on a biodegradable polymer such as poly (D, L-lactide) (PLA), polyglycolide (PHA) and a copolymer of D, L-lactide and glycolide (PLHA). 7. The pharmaceutical composition according to claim 6, which is a composition for oral administration. 8. The pharmaceutical composition according to claim 7, containing sustained release pellets, containing: (i) inert pellet core; (ii) a drug layer comprising said pellet core, said drug layer containing an active agent containing pramipexole, rasagiline, or both of these substances, or pharmaceutically acceptable salts thereof, optionally mixed with a binding agent and / or film-forming polymer and optionally further mixed with a glidant; (iii) an optionally insulating / protective subcover layer comprising said drug layer; and (iv) a sustained release coating layer comprising said subcover layer, if present, or said drug layer. 9. The pharmaceutical composition according to claim 8, characterized in that said subcoat layer comprises a film-forming polymer and, optionally, a glidant. 10. The pharmaceutical composition according to p. 9, characterized in that the said release coating layer contains: (i) at least one pH independent polymer and, optionally, a pore forming agent, wherein the sustained release pellet has pH independent in vitro release characteristics; (ii) a pH independent polymer, a hydrophilic release modulator polymer and, optionally, a hydrophobic or hydrophilic plasticizer and / or glidant; or (iii) a mixture of a pH dependent enteric coating polymer and a pH independent polymer, wherein the sustained release pellet has approximately zero order in vitro release characteristics at a pH of not more than 7.4. 11. The pharmaceutical composition according to p. 8, characterized in that: (i) said binding agent is polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose, or a combination thereof; (ii) said film-forming polymer is PVP, HPMC, HPC, microcrystalline cellulose, or a combination thereof; and (iii) said glidant is talc, colloidal silicon dioxide, glyceryl monostearate, or a combination thereof. 12. The pharmaceutical composition according to p. 9, characterized in that: (i) said pH independent polymer is ethyl cellulose, a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methactylate chloride in a ratio of 1: 2: 0.2, respectively, a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride in a ratio of 1: 2: 0.1, respectively, a copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2: 1, respectively, or a combination thereof; (ii) said pH dependent enteric coating polymer is a copolymer of methyl acrylic acid and methyl methacrylate in a ratio of 1: 2, respectively, a copolymer of methyl acrylate and ethyl acrylate in a ratio of 1: 1, respectively, graft copolymer of polyethylene glycol with polyvinyl alcohol, hydroxypropyl methylcellulose phthalate (FGPMTs), alginates carboxymethyl cellulose or a combination thereof; (iii) said pore-forming agent is PVP, PEG, HPMC, HPC, methyl cellulose, 1,2-propylene glycol, lactose, sucrose, talc or a combination thereof; (iv) said hydrophilic release polymer modulator is HPMC, HPC, PVP, PEG, or a combination thereof; and (v) said plasticizer is dibutyl sebacate; dibutyl phthalate; citric acid esters such as triethyl citrate and triacetin; propylene glycol; low molecular weight poly (alkylene oxides) such as PEG, poly (propylene glycols) and poly (ethylene / propylene glycols), or a combination thereof. 13. The pharmaceutical composition according to claim 8, characterized in that the said sustained release pellet contains: (i) inert pellet core; a drug layer containing said active agent in admixture with PVP used as a film-forming polymer / binding agent and highly dispersed talcum powder used as a glidant; and a sustained release (ER) coating layer containing ethyl cellulose as a pH independent polymer and PEG as a pore forming agent, wherein the amount of said film forming polymer / binding agent is up to 90% by weight of the total weight of the drug layer or from 0.5 up to 20% by weight of the total weight of the pellets; the amount of said glidant is up to 30% by weight of the total weight of the drug layer or from 0.1 to 10% by weight of the total weight of the pellet; the amount of said pH-independent polymer is from 50 to 90% by weight of the total weight of the ER coating layer or from 10 to 30% by weight of the total weight of the pellet and the amount of said pore-forming agent is from 1 to 20% by weight of the total weight of the layer ER coatings or from 0.1 to 10% by weight of the total weight of the pellets; or (ii) inert pellet core; a drug layer containing the specified active agent in admixture with PVP used as a film-forming polymer / binding agent and highly dispersed talcum powder used as a glidant; an insulating / protective undercover layer containing PVP as a film-forming polymer; and an ER coating layer containing ethyl cellulose as a pH independent polymer, PEG as a pore forming agent and highly dispersed talc as a glidant, wherein the amount of said film forming polymer / binding agent included in said drug layer is up to 90 % by weight of the total weight of the drug layer or from 0.5 to 20% by weight of the total weight of the pellet; the amount of said glidant that is part of said drug layer is up to 30% by weight of the total weight of the drug layer or from 0.1 to 10% by weight of the total weight of the pellet; the amount of the specified film-forming polymer, which is part of the specified subcover layer, is up to 100% by weight of the total mass of the subcover layer or from 0.5 to 20% by weight of the total weight of the pellet; the amount of said pH-independent polymer is from 50 to 90% by weight of the total weight of the ER coating layer or from 10 to 30% by weight of the total weight of the pellet; the amount of the specified pore-forming agent is from 1 to 20% by weight of the total weight of the ER coating layer or from 0.1 to 10% by weight of the total weight of the pellets and the amount of the specified slip promoter included in the specified ER-coating layer, is from 0.1 to 20% by weight of the total mass of the ER coating layer or from 0.1 to 10% by weight of the total weight of the pellet. 14. The pharmaceutical composition according to any one of paragraphs. 7-13, characterized in that said sustained release pellets are mixed with one or more suitable excipients and either they are placed in a capsule or compressed into a tablet, and said capsule or tablet contains extended release pellets containing pramipexole, and sustained release pellets containing razagilin or sustained release pellets containing pramipexole and rasagiline. 15. A method of obtaining a sustained release composition containing a combination of pramipexole and rasagiline or their pharmaceutically acceptable salts with fixed doses, where the specified combination with fixed doses contains from 0.05 to 1.0 mg of pramipexole and from 0.055 to 1.0 mg of rasagiline , and the method comprises the steps of: (i) dissolving the active agent containing pramipexole, rasagiline or both of these substances in a suitable solvent system to obtain a uniform suspension; (ii) coating the suspension obtained in step (i) on inert pellets, such as inert nonpareil grains; (iii) applying to the pellets obtained in stage (ii), a sustained release coating layer that provides a sustained release of said pramipexole and rasagiline, thereby obtaining said sustained release formulation; (iv) mixing the coated pellets obtained in step (iii) with a suitable excipient; and (v) filling capsules with said sustained release formulation or compressing said sustained release formulation into tablets, said capsules or tablets having a ratio of pellets containing pramipexole to pellets containing rasagiline selected from the range 1: 1.1-1: 20 ; 1: 1.1-1: 10; 1: 1.1-1: 5; 1: 1.1-1: 3 or 1: 1.1-1: 2; or said capsules or tablets contain pellets containing pramipexole and razagiline in a ratio selected from the range of 1: 1.1-1: 20, 1: 1.1-1: 10, 1: 1.1-1: 5, 1: 1.1-1: 3 or 1: 1.1-1: 2, thereby obtaining a sustained release composition containing a combination of pramipexole and rasagiline with their fixed doses. 16. The method according to p. 15, characterized in that said active agent from step (i) or a pharmaceutically acceptable salt thereof is suitably mixed (a) with a binding agent and / or a glidant. 17. The method according to p. 15, further comprising applying an insulating / protective undercover layer to pellets containing razagiline, pellets containing pramipexole, or pellets containing pramipexole and rasagiline obtained in stage (ii), to obtain pellets coated with said insulating / protective undercover. 18. The method according to p. 17, further comprising applying to the pellets coated with an insulating / protective undercover layer, a sustained release coating layer that provides a sustained release of said pramipexole and rasagiline, thereby producing pellets coated with a sustained release coating layer, and obtaining the specified composition with prolonged release. 19. The method according to p. 18, further comprising mixing said pellets coated with a sustained release layer with a suitable excipient.

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